Macrophages Expressing GALC Improve Peripheral Krabbe Disease by a Mechanism Independent of Cross-Correction

• Published in: Neuron (Cambridge, Mass.) Vol. 107; no. 1; pp. 65 - 81.e9
• Main Authors: Weinstock, Nadav I., Shin, Daesung, Dhimal, Narayan, Hong, Xinying, Irons, Eric E., Silvestri, Nicholas J., Reed, Chelsey B., Nguyen, Duc, Sampson, Oliver, Cheng, Yung-Chih, Lau, Joseph T.Y., Bongarzone, Ernesto R., Kofler, Julia, Escolar, Maria L., Gelb, Michael H., Wrabetz, Lawrence, Feltri, M. Laura
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.07.2020; Elsevier Limited
• Subjects: Animals; cross-correction; Demyelinating Diseases - enzymology; Demyelinating Diseases - pathology; Demyelination; Enzymes; Fibroblasts; Galactosylceramidase - metabolism; Galactosylceramide; GALC; Genotype & phenotype; globoid cell leukodystrophy; hematopoietic stem cell therapy; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Humans; Inflammation; Krabbe disease; Leukodystrophy; Leukodystrophy, Globoid Cell - enzymology; Leukodystrophy, Globoid Cell - pathology; Leukodystrophy, Globoid Cell - therapy; Lysosomal enzymes; Lysosomal storage diseases; lysosomal storage disorder; lysosomes; macrophage; Macrophages; Macrophages - enzymology; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin; Nerve Degeneration - enzymology; Nerve Degeneration - pathology; Nerves; Neurodegeneration; Phagocytes; Phenotypes; psychosine; Schwann cell; Schwann cells; Schwann Cells - enzymology; Stem cell transplantation; GALC; psychosine; galactosylceramide; Schwann cell; Krabbe disease; demyelination; hematopoietic stem cell therapy; macrophage; globoid cell leukodystrophy; lysosomes; cross-correction; lysosomal storage disorder
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2020.03.031

Many therapies for lysosomal storage disorders rely on cross-correction of lysosomal enzymes. In globoid cell leukodystrophy (GLD), mutations in GALC cause psychosine accumulation, inducing demyelination, a neuroinflammatory “globoid” reaction and neurodegeneration. The efficiency of GALC cross-correction in vivo, the role of the GALC substrate galactosylceramide, and the origin of psychosine are poorly understood. Using a novel GLD model, we show that cross-correction does not occur efficiently in vivo and that Galc-deficient Schwann cells autonomously produce psychosine. Furthermore, macrophages require GALC to degrade myelin, as Galc-deficient macrophages are transformed into globoid cells by exposure to galactosylceramide and produce a more severe GLD phenotype. Finally, hematopoietic stem cell transplantation in patients reduces globoid cells in nerves, suggesting that the phagocytic response of healthy macrophages, rather than cross-correction, contributes to the therapeutic effect. Thus, GLD may be caused by at least two mechanisms: psychosine-induced demyelination and secondary neuroinflammation from galactosylceramide storage in macrophages. [Display omitted] •Schwann cell Galc prevents psychosine-induced demyelination and neurodegeneration•GALC transfer (cross-correction) is minimal in globoid cell leukodystrophy (GLD) cells•Storage-laden macrophages (globoid cells) are direct mediators of GLD pathogenesis•HSCT for GLD provides functional macrophages that are competent of phagocytosis Weinstock et al. show that lysosomal GALC is required autonomously by Schwann cells to prevent psychosine formation, demyelination, and subsequent axonal degeneration. Macrophages independently require GALC to serve in phagocytosis and myelin turnover. HSCT likely exerts its therapeutic benefit by restoring phagocyte function rather than cross-correcting myelin cells of GALC.